Idorsia sets itself up for failure
Cenerimod flunks a mid-stage lupus study, so Idorsia moves to go straight into phase 3. What can possibly go wrong?
Idorsia’s faith in cenerimod might be understandable in the context of lupus recently becoming an area for deal-making interest. But the group’s decision to press on into phase 3 trials after cenerimod today flopped in phase 2 seems reckless, and potentially sets the project up for an even bigger failure later on.
True, Idorsia has plenty of cash to burn – over CHF1bn ($1.1bn) of short-term liquidity at the end of September, to be precise – but its investors should today ask whether starting a large pivotal programme is wise. At best one cenerimod dose has shown hints of activity, but first running a confirmatory phase 2 trial to test this hypothesis prospectively would be more prudent.
The Care study toplined today tested four doses of cenerimod, an S1P receptor modulator. The highest, 4mg, showed a numerical improvement in the primary endpoint, mSLEDAI-2K score versus placebo at six months, Idorsia said today without giving any further efficacy details apart from revealing a nominal p value of 0.029 for the 4mg dose.
On the face of it this does seem promising, even ignoring the fact that, given the statistical penalty for analysing the four doses separately, the p value was highly non-significant.
But seasoned biotech investors will be aware that any benefit reported in a mid-stage trial would be expected to wane in the stricter setting of phase 3. We do not know the absolute benefit shown by cenerimod 4mg, but even a nominal p of 0.029 is hardly an overwhelming signal of efficacy, and such a borderline effect would be expected to be at an especially high risk of melting away in a pivotal trial.
Moreover, Idorsia appears to be hinting that there is a numerical dose-response effect in Care, but importantly it has not actually spelled this out. If the highest dose has done best this is clearly good, but Idorsia has revealed nothing about the numerical performance of any of the lowest three cenerimod doses.
Idorsia says 4mg was also associated with improvements in several patient subpopulations, especially those with severe disease, and on the SLE responder index, a four-point composite measure of activity in lupus. It did not say whether either would be incorporated into the phase 3 programme it now aims to discuss with regulators.
Finally, if 4mg is so good, with no toxicity penalty, why not test an even higher dose? The disappointment is the second to hit Idorsia in recent weeks; in mid-October its Fabry disease project lucerastat failed a pivotal study.
S1P modulation is more commonly associated with drugs for multiple sclerosis, including Novartis’s Gilenya and Mayzent, and Idorsia/J&J’s recently approved Ponvory. Another positive for cenerimod, which Idorsia describes as highly selective with a bias for the S1P1 subtype, is that it had no impact on blood pressure or pulmonary function, which S1P1 receptor modulators are known to affect.
Still, this mechanism has hardly proved a resounding success in lupus. According to Evaluate Pharma two other projects, the S1P1/4/5 agonist prodrug KRP-203 and the S1P1 receptor antagonist amiselimod, were once studied in the disease, but they have seen no work since 2017.
Cenerimod carried modest sellside revenue forecasts, $108m in 2026, according to Evaluate Pharma, but these were likely predicated on Care serving as one registrational study, and a single phase 3 sufficing as the other. There will now be a lengthy delay while Idorsia undertakes two new phase 3 tests, whose likelihood of success must now be seen as remote.
|Selected lupus projects acting on S1P (sphingosine-1-phosphate)|
|Project||Company||Mechanism||Lupus summary||Other indications|
|Cenerimod||Idorsia||S1P1 receptor modulator||Moving to ph3 after failing ph2||None|
|Mocravimod (KRP-203)||Kyorin/Novartis||S1P1/4/5 agonist prodrug||Abandoned after ph2||Ph2 in ulcerative colitis terminated|
|Amiselimod (MT-1303)||Biogen/Mitsubishi Chemical||S1P1 receptor inhibitor||Abandoned after ph1||Ph2 in ulcerative colitis enrolling; ph2 in relapsing/remitting MS completed|
|Source: Evaluate Pharma & clinicaltrials.gov.|